期刊
BIOMATERIALS
卷 192, 期 -, 页码 429-439出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.biomaterials.2018.06.020
关键词
ABT-199; Bcl-2; Nanotechnology; Targeted drug delivery; Mitochondria; Allergic airway inflammation
资金
- National Key Research and Development Program of China [2016YFA0203600, 2016YFA0100301]
- National Natural Science Foundation of China [81130001, 81490532, 31822019, 51503180, 51611540345, 31370901, 81422031, 81870007, 81700023, 51703195, 51502251, 81571743, 91642202]
- Key Project of Chinese National Programs for Fundamental Development (973 program) [2015CB553405]
- Open Project of State Key Laboratory of Respiratory Disease [SK 25 LRD2016OP002]
- National Key Technologies R&D Program for the 12th Five-year Plan [2012BAI05B01]
- Key Science Technology Innovation Team of Zhejiang Province [2011R50016]
- Natural Science Foundation of Zhejiang Province, China [LD19H160001]
- Fundamental Research Funds for the Central Universities [2015XZZX004-16, 520002*172210161]
- National 1000 Talents Program for Distinguished Young Scholars
- Fundamental Research Funds for Xiamen University [20720160067]
Elimination of airway inflammatory cells is essential for asthma control. As Bcl-2 protein is highly expressed on the mitochondrial outer membrane in inflammatory cells, we chose a Bcl-2 inhibitor, ABT-199, which can inhibit airway inflammation and airway hyperresponsiveness by inducing inflammatory cell apoptosis. Herein, we synthesized a pH-sensitive nanoformulated Bcl-2 inhibitor (Nf-ABT-199) that could specifically deliver ABT-199 to the mitochondria of bronchial inflammatory cells. The proof-of-concept study of an inflammatory cell mitochondria-targeted therapy using Nf-ABT-199 was validated in a mouse model of allergic asthma. Nf-ABT-199 was proven to significantly alleviate airway inflammation by effectively inducing eosinophil apoptosis and inhibiting both inflammatory cell infiltration and mucus hypersecretion. In addition, the nanocarrier or Nf-ABT-199 showed no obvious influence on cell viability, airway epithelial barrier and liver function, implying excellent biocompatibility and with non-toxic effect. The nanoformulated Bcl-2 inhibitor Nf-ABT-199 accumulates in the mitochondria of inflammatory cells and efficiently alleviates allergic asthma. (C) 2018 Published by Elsevier Ltd.
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